超高载药量乏氧响应性仿生纳米药物的构建及其用于晚期乳腺癌靶向治疗的研究

纳米药物用于治疗晚期乳腺癌的关键在于如何实现药物的高效包载、靶向递送和肿瘤部位的特异性释放。本项目发展一种具有超高载药量、中性粒细胞膜包衣的靶向药物递送体系，用于解决药物的靶向递送和抗肿瘤治疗过程中的几个关键问题：（1）设计紫杉醇二聚体前药，通过二聚体结构削弱药物之间的π-π相互作用，实现药物的高效包载。（2）设计中性粒细胞膜包衣的纳米药物，通过肿瘤组织招募、肿瘤微环境炎症刺激的激活，实现对肿瘤细胞、循环肿瘤细胞的有效靶向。（3）设计乏氧敏感的紫杉醇二聚体前药，利用晚期乳腺癌瘤内严重的乏氧环境，实现肿瘤部位药物的特异性释放，提高抗肿瘤疗效。本项目对实现纳米药物的高效载药和靶向抗肿瘤治疗具有重要意义。

The efficient encapsulation of drugs in nanomedicine, targeted delivery of drugs into tumor cells, and the specific release of drugs in tumors serve as the critical challenges for the successful treatment of advanced breast cancer. In the current study, we aim to develop the neutrophil membranes coated nanoparticles with high drug loading to solve these critical challenges against targeted anticancer therapy. (1) We synthesize the paclitaxel (PTX) dimer to achieve high drug loading by reducing the π-π interaction between drugs. (2) We design the neutrophil membranes coated nanoparticles that can be recruited by tumor tissue and further activated by inflammatory stimuli in tumor microenvironment to achieve targeted anticancer treatment of tumor cell and circulating tumor cell. (3) Based on the severe hypoxic environment in advanced breast cancer, we design the hypoxia-responsive PTX dimer that can realize specific PTX release in tumor site to enhance anticancer efficacy. This study provides a useful strategy for efficient drug loading and targeted anticancer therapy.